<jats:title>Abstract</jats:title><jats:p>Malignant mesothelioma (MM) is still increasing worldwide. The pathogenesis depends on asbestos‐induced iron accumulation, which eventually leads to ferroptosis‐resistance of mesothelial cells via somatic mutations. Poly (<jats:italic>rC)</jats:italic>‐binding proteins 1 and 2 (PCBP1/2) are recently recognized cytosolic Fe(II) chaperones. Here we studied the role of PCBP1/2 in rat/human mesothelial and MM cells as well as rat/human MM specimens. Normal peritoneal mesothelial cells in rats exhibited PCBP1 but not PCBP2 immunopositivity whereas primary/immortalized mesothelial cells showed PCBP1/2 immunopositivity. Rat MM specimens induced by intraperitoneal injection of chrysotile, including in situ lesion, revealed PCBP1/2 immunopositivity (90% for both) in the nucleus and cytoplasm with a tendency of higher expression in epithelioid subtype. Knockdown of <jats:italic>PCBP2</jats:italic> but not <jats:italic>PCBP1</jats:italic> significantly decreased both TfR1 and FTH expression in MM cells with inhibition of proliferation, indicating stagnation of intracellular iron transport. Erastin, a cysteine‐deprivation type ferroptosis inducer, decreased the expression of both PCBP1/2 in MM cells. Furthermore, <jats:italic>PCBP2</jats:italic> knockdown significantly increased the sensitivity of MM cells to erastin‐induced ferroptosis with increased catalytic Fe(II). In conclusion, PCBP2 works for ferroptosis‐resistance not only during mesothelial carcinogenesis but also in MM, which warrants further investigation as a novel therapeutic target.</jats:p>